Interleukin-6: Neurologic Impact in Rheumatoid Arthritis


This inflammatory cytokine may be linked to many of the secondary neuroendocrine and psychological symptoms of RA.

Key points
• Interleukin-6 inhibitors such as tocilizumab, sarilumab, and sirukumab have a positive effect on patient-reported pain in rheumatoid arthritis (RA).
• Evidence supports the role of interleukin-6 and the hypothalamic–pituitary–adrenal axis in the development of RA-related fatigue.
• A significant reduction in fatigue was found in patients with RA treated with biologic agents.
• There appears to be a link between interleukin-6 and mood disorders.
• The anti-interleukin 6 drugs tocilizumab, sarilumab, and sirukumab have been shown to reduce mood-related complaints in phase 3 studies.

In addition to joint pain and destruction, patients with RA suffer more from fatigue, mood disorders, and pain than the general population.

It is well known that cytokines such as interleukin-6 are elevated in RA. Dr. Ernest Choy at Cardiff University in Wales and Dr. Leonard Calabrese at the Cleveland Clinic in Ohio sought to determine the translational effects of interleukin-6 in patients with RA with regards to pain, fatigue, and mood disorders. They present the results of their literature review in a recent Rheumatology article.

The study
The authors conducted a systematic literature review of peer-reviewed primary articles published since 2005. The review included phase 2 or higher clinical trials that reported pain, fatigue, or mood and also included preclinical mechanistic studies.

The resultsPain
• Preclinical evidence suggests that interleukin-6 plays a large role in pain mechanisms related to RA.

• The interleukin-6 signal transducer gp130 is a key regulator in the development of mechanical hypersensitivity associated with inflammation.

• In a rat model of inflammatory arthritis, injections of gp130 significantly reduced pain.

• Multiple trials, including the Tocilizumab Pivotal Trial in Methotrexate Inadequate Responders, Tocilizumab Safety and Prevention of Structural Joint Damage, Tocilizumab and DMARDs: Achievements in Rheumatoid Arthritis, and the Actemra Versus Methotrexate Double-blind Investigative Trial in Mono-therapy studies, showed significant pain improvement down to slight improvement in the respective reports.

• Sirukumab produced a dose-dependent improvement in the A Study of CNTO 136 (Sirukumab), a Human Anti-IL-6 Monoclonal Antibody, Administered Subcutaneously, in Patients With Active Rheumatoid Arthritis Despite Anti-TNF-Alpha Therapy study.

• The probability of developing fatigue was associated with mood disorders, pain, and disability or diminished physical functioning.

• Low levels of cortisol, a product of the hypothalamic-pituitary-adrenal (HPA) axis, are associated with chronic fatigue.

• Interleukin-6 plays a pivotal role in stimulating the HPA axis.

• Patients with RA have impaired activity of the HPA axis compared with the general population.

• A significant reduction in fatigue was found in patients with RA who were treated with biologic anti-rheumatic drugs, including interleukin-6 inhibitors.

Mood disorders
• Animal models treated with interleukin-6 inhibitors or lacking interleukin-6 altogether showed resilience to social stress.

• Lower levels of interleukin-6 predict earlier resolution of negative mood.

• Interleukin-6 is the most consistently elevated cytokine in patients with major depressive disorder.

• Phase 3 studies that looked at tocilizumab, sarilumab, and sirukumab showed improvements in mood following treatment with interleukin-6 inhibitors.

Implications for physicians
• While it is known that interleukin-6 plays a major role in the pathogenesis of RA, it now appears that many of the secondary neuroendocrine and psychological symptoms are linked to this inflammatory cytokine.

• When prescribing interleukin-6 inhibitors for rheumatoid arthritis, physicians may choose to counsel patients that therapy may also improve pain, mood, and fatigue symptoms.

• Although links are apparent between interleukin-6 inhibition, the HPA axis, pain, mood, and fatigue, more study beyond preclinical trials is needed to truly define the association and guide treatment.


No funding sources were reported.


Choy EHS, Calabrese LH. Neuroendocrine and neurophysiological effects of interleukin 6 in rheumatoid arthritis. Rheumatology (Oxford). 2017 Nov 22. doi: 10.1093/rheumatology/kex391. [Epub ahead of print]

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